Technical Field
Molecules are needed that modulate the immune response, such as for enhancing the immune response specific to a pathogen or to a tumor cell and for suppressing an autoimmune response, and that have minimal or no associated toxic effects. A class of signaling molecules that modulates the immune response and uses of these molecules are described herein.
Description of the Related Art
The innate immune response (or antigen non-specific or antigen independent immune response) is the first immune defense mechanism marshaled by a host in response to an infectious microorganism or other antigens recognized as non-self. Natural killer T (NKT) cells are a conserved T lymphocyte subpopulation that regulates multiple types of immune responses. Invariant natural killer T (iNKT) cells are a subset of these lymphocytes involved in the innate immune response. The iNKT cells recognize lipid antigens bound to the MHC class I-related molecule CD1d that is expressed by antigen presenting cells (APCs) (such as dendritic cells). In response to glycolipids, the iNKT cells produce large amounts of cytokines that leads to downstream activation of dendritic cells, natural killer (NK) cells, B cells, and T cells. Therefore, the iNKT cells modulate autoimmune diseases, inflammation, tumor resistance, and anti-microbial responses.
A non-mammalian glycosphingolipid, α-galactosylceramide (α-GalCer) such as KRN 7000, a glycosphingolipid derived from the sponge, Agelas mauritianus, has been studied and investigated in clinical trials (see, e.g., International Patent Application Publication No. WO 98/29534; Morita et al., Biosci. Biotechnol. Biochem. 60:288-92 (1996)). KRN 7000 has not achieved success, at least in part, because the cytokines produced by activated NKT cells cause an antagonistic effect, limiting its usefulness (see, e.g., Bancet-Cadeddu et al., Org. Biomol. Chem. 9:3080-104 (2011)).
Accordingly, identifying and developing other glycosphingolipid molecules is desirable for use as immunotherapeutic agents. The molecules and uses described herein address this unmet medical need.